Project Summary/Abstract Anorexia Nervosa affects up to 2% of women in the US and is characterized by extreme, self-induced starvation. Of the many medical co-morbidities associated with this disorder, severe bone loss is the most common and often persists despite weight recovery. Importantly, this bone loss is associated with an increased risk of fracture; a prospective study demonstrated that women with anorexia nervosa have a 7-fold increased risk of fracture compared to age-matched controls. Therefore, a treatment to prevent the severe bone loss associated with this disease is critical, but there are currently no approved treatments for anorexia nervosa- associated bone loss. We have recently shown that 6 months of treatment with teriparatide increases lumbar spine bone mineral density (BMD) by 6% in women with anorexia nervosa but use of teriparatide is only approved for 24 months and the majority of patients live with this disease for decades. Bisphosphonates, which increase BMD by 3-4% after 12 months of use, also have potential harmful effects with long-term use (ie atypical femoral fractures with prolonged use). Therefore, an optimal treatment for bone loss in this disease will not only effectively increase BMD, but will also be available for long-term use. Amenorrhea and resultant hypoestrogenemia -- characteristic findings in women with anorexia nervosa -- are significant contributors to the loss of bone mass in this disease. This is supported by the fact that duration of amenorrhea is directly associated with low BMD in women with anorexia nervosa. Yet, despite this association, multiple studies investigating the effects of oral estrogen in women with anorexia nervosa have not demonstrated a benefit. Recently, transdermal estrogen has been shown to increase BMD in adolescent girls with anorexia nervosa but whether transdermal estrogen will improve BMD in women with anorexia nervosa is not known. Prior treatment studies have demonstrated distinctly different responses to treatments in adolescents with anorexia nervosa as compared to adults. For example, although BMD in adult women increases by 3-4% in response to one-year of bisphosphonate treatment, adolescents treated with bisphosphonates for one-year do not have a significant increase in BMD compared to those treated with placebo. Therefore, treatments that may be effective in one population may not be effective in the other. Our preliminary data demonstrate a 2.1% increase in spine BMD in women with anorexia nervosa treated with 6 months of transdermal estrogen replacement coupled with a decrease in marrow adipose tissue, a potential determinant of bone mass. Therefore, we propose to perform a randomized, double-blind placebo-controlled study to investigate the effects of transdermal estrogen replacement on bone mass, bone microarchitecture and marrow adipose tissue in adult women with anorexia nervosa. By investigating associations between changes in bone mass, bone turnover markers and marrow adipose tissue in response to transdermal estrogen, we also hope to gain a greater understanding of the pathophysiology of bone loss in states of chronic undernutrition.